Sir Hans Adolf Krebs was a German biochemist and a true specialist for elucidating cyclic metabolic pathways, i.e. cyclic series of chemical reactions in a cell. He is credited with the discovery of three such pathways, the ornithine cycle, the glyoxylate cycle and – most importantly – the citric acid or Krebs cycle. In the Krebs cycle, acetate, originating from the degradation of sugars or fatty acids, is further degraded to carbon dioxide, thereby yielding energy in the form of ATP and GTP molecules. The intermediates of the cycle are also important precursors for the synthesis of other biomolecules, such as amino acids. In total, the Krebs cycle accounts for two thirds of the oxidation of carbon compounds in most cells [1]. It thus appears to be fair to consider it the most important metabolic process altogether.In 1937, Krebs and his graduate student William A. Johnson attempted to publish their groundbreaking discovery in the journal Nature. Surprisingly, their article, which should turn out to be one of the most important biological papers of the 20th century, was rejected [2]. It eventually appeared in another journal, Enzymologia [3]. In the present lecture, which was given more than 40 years after this publication, Krebs takes a look back and considers a seemingly trivial question. Why is the citric acid cycle a cycle? Why is it not a linear pathway? Krebs claims to have been unable to answer this question, which was repeatedly asked by his students, until 1980, when he discussed the issue with his Oxford colleague, Jack Baldwin, a professor of organic chemistry and true specialist of reaction mechanisms.Baldwin suggested that the cyclic nature of the oxidation of acetate may have evolutionary reasons. Naturally, evolution would prefer the mechanism which yields most energy, that is most ATP molecules. Whereas a non-cyclic process, based on the direct oxidation of acetate, would be thinkable, it would have to involve several unfavorable reaction mechanisms, thus yielding less ATP. The intermediates of the citric acid cycle, on the other hand, allow for very efficient enzymatic reactions and thus ensure that the maximum possible amount of ATP molecules is generated from each acetate unit entering the cycle.In concluding his talk, Krebs expresses his concern about a tendency of overmedication in modern medicine. According to Krebs, physicians should always stay aware of the ultimate degree of optimization and efficiency Nature has achieved for metabolic processes. This quasi-perfect status quo makes it very unlikely, that a drug tampering with metabolism will ever change anything for the better, Krebs says. His statement, which is now more than 30 years old, could not be more topical: drug side-effects are estimated to be the fourth to sixth leading cause of death in the United States today [4]. The present lecture is the last of nine lectures Krebs gave in Lindau from 1960 to 1981. He passed away in Oxford only five months later, on November 22nd.David Siegel[1]B. Alberts et al., Molecular Biology of the Cell, Fifth Edition, 2008, Garland Science, New York, USA. [2]H. Kornberg, Nature Reviews Molecular Cell Biology 2000, volume 1, pages 225-228.[3]H. A. Krebs and W. A. Johnson, Enzymologia 1937, Volume 4, pages 148-156. [4]J. Lazarou et al., Journal of the American Medical Association 1998, volume 279,pages 1200-1205.